Project Summary/Abstract Beige (brown) adipocytes convert energy (food, fat, glucose) to heat, a feature of potential therapeutic benefit for obesity and diabetes. Our overall objective is to elucidate the mechanisms that control formation of beige adipocytes and to determine whether and how these processes might be harnessed to treat metabolic diseases, which are at epidemic proportion. Thus there is an urgent need to better understand the mechanisms and molecules that control adiposity and glucose homeostasis. Clinical trials studying young adults show that daily cold exposure induces beige adipocyte formation, increases energy expenditure, and reduces adiposity and glucose levels. This process fails during aging, in concert with decreasing energy expenditure, increasing adiposity and diabetes incidence. That new beige adipocytes form, at least in younger adults, indicates the presence of a putative cold-inducible beige adipogenic stem cell/progenitor. Yet major barriers to unraveling this cold-inducible beige adipose progenitor compartment include lack of reagents, tools, and methods to study and manipulate the progenitor, and the lack of understanding of age-dependent dysfunction, a major clinical impediment. Our published work indicate that we addressed some of these issues, and identified cold-inducible beige adipose progenitors by designing, engineering, and studying mice that express molecular reporters and inducible gene switches in the beige progenitor compartment. These tools enable us to visualize cold-inducible beige adipose progenitors in vivo, to follow their descendants as they divide, migrate and develop into mature beige adipocytes. The tools also allow us to interrogate and manipulate gene function within this key progenitor population. With such approaches, we found that senescence causes the age-dependent failure to induce beige cells in the cold, and that we could reverse the process and rejuvenate old progenitors to produce beige adipocytes through innovative genetic approaches and with drugs. The central focus of this proposal is to use our new tools to delineate the in vivo functions and molecular characteristics of cold-inducible beige adipocyte progenitors, and their age-dependent failure to function; our Preliminary Studies identify novel control mechanisms. We will define these mechanistic underpinnings, we will understand how physiological and pharmacological stimuli regulate the progenitor population, energy expenditure, and adiposity, and we will exploit these insights to therapeutic ends. Our studies are designed to elucidate new aspects of adipose biology and metabolic control, highlighting those that are particularly relevant to new therapies for obesity and diabetes.